Nuclear reprogramming defines the dedifferentiation of adult cells into pluripotent[unreadable] embryonic cells and has enormous therapeutic potential as it allows generating[unreadable] genetically matched cells from patients for cell therapy. Reprogramming has so far been[unreadable] achieved by nuclear transfer into oocytes and by cell fusion between embryonic cells and[unreadable] somatic cells, two approaches that have serious technical or ethical limitations. Based on[unreadable] recently published observations, we have generated so-called induced pluripotent stem[unreadable] (iPS) cells directly from fibroblasts by retroviral overexpression of the transcription[unreadable] factors Oct4, Sox2, c-myc and Klf4. In contrast to the previously reported iPS cells, our[unreadable] iPS cells were indistinguishable from ES cells in their epigenetic state and developmental[unreadable] potential. Several crucial questions were raised by these findings; (i) what is the sequence[unreadable] of molecular changes that accompany nuclear reprogramming, (ii) what is the kinetics of[unreadable] reprogramming and does it require cell division, (iii) are different cell types at different[unreadable] differentiation stages equally amenable to reprogramming, and (iv) can human cells be[unreadable] reprogrammed into iPS cells? Resolving these questions will be critical for understanding[unreadable] the molecular nature of nuclear reprogramming and may lead to strategies that allow[unreadable] efficient reprogramming of patient?s cells into pluripotent cells. The current limitations to[unreadable] solve these questions are the low efficiency of direct reprogramming and the inability to[unreadable] follow reprogramming in real time. We will tackle these questions by generating[unreadable] ?reprogrammable mice? in which every single cell can be reversibly induced to express[unreadable] the four factors at levels necessary for reprogramming, and by attempting to reprogram[unreadable] human cells. The goals of this proposal are thus to determine (i) the robustness and[unreadable] kinetics of reprogramming, (ii) the hierarchy of transcriptional and epigenetic changes[unreadable] that accompany nuclear reprogramming, (iii) the responsiveness of different cell types to[unreadable] the four factors, and (iv) the feasibility of human reprogramming.